INTRATHYMIC INJECTION OF DONOR-SPECIFIC X-IRRADIATION-SENSITIVE SPLEEN-CELLS ABROGATES ACCELERATED REJECTION OF CARDIAC ALLOGRAFTS IN SENSITIZED RATS

LBNF(1) cardiac allografts are rejected within 36 hr in Lewis (LEW) ra ts sensitized with Brown Norway (BN) skin grafts (acute rejection = 7. 5 days). We analyzed the effects of intrathymic versus intravenous all oantigen challenge upon graft survival in this well defined accelerate d rejection model. Intrathymic injection of LBNF(1) spleen cells (2x10 (7)) at the time of skin transplantation (day -7) abrogated < 36 hr re jection, and prolonged the survival of cardiac allografts to about 11 days. This striking effect did not require concomitant immunosuppressi on, and was donor specific, as the transfer of syngeneic (LEW) or thir d-party (Wistar-Furth) splenocytes was ineffective. X-irradiation of d onor spleen cells before inoculation restored accelerated rejection, w hereas thymectomy at day -6 or 0 (the day of heart transplant) signifi cantly shortened graft survival. In contrast, although intravenous adm inistration of the same number of donor cells into sensitized recipien ts prolonged cardiac allograft survival to about 9 days, the effect wa s x-irradiation resistant and was never influenced by thymectomy. Radi oactive tracer studies have revealed distinct trafficking patterns for the transferred cells, with those given intrathymically retained most ly in the thymus, and sequestered into host spleen and lymph nodes. In stead, intravenously injected splenocytes did not accumulate in the th ymus, but were eventually trapped in the liver. Moreover, intrathymic immunomodulation has switched off cellular, rather than humoral, event s at the graft site, and markedly depressed cell proliferative respons es in host lymphoid organs, as analyzed by immunohistology and mixed l ymphocyte response (MLR) assay, respectively. In contrast, intravenou s therapy did not have any significant effect on early intragraft cell ular infiltration, including considerable neutrophil infiltration, and did not affect lymph node cell proliferation in vitro. These data doc ument the importance of the thymus as a potential target organ for mod ulation of alloreactivity in vivo, and reinforce the role of distinct ''central'' and ''peripheral'' host immune mechanisms contributing to immunological unresponsiveness following organ transplantation.